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International Journal of Molecular... May 2021Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the...
Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial-mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease.
Topics: Genetic Diseases, X-Linked; Humans; Kidney Tubules, Proximal; Lab-On-A-Chip Devices; Models, Biological; Mutation; Nephrolithiasis; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 34069732
DOI: 10.3390/ijms22105361 -
Kidney Diseases (Basel, Switzerland) Apr 2023Diabetic kidney disease (DKD) is a major source of chronic kidney disease and end-stage renal disease. The injury of glomerulus in DKD is the primary focus; however,...
INTRODUCTION
Diabetic kidney disease (DKD) is a major source of chronic kidney disease and end-stage renal disease. The injury of glomerulus in DKD is the primary focus; however, proximal tubulopathy also is an indispensable factor in the progression of DKD. Interleukin-37 (IL-37), an anti-inflammatory cytokine of IL-1 family member, has been demonstrated to be associated with diabetes and its relative complications in recent years, but the effect of IL-37 on renal fibrosis in DKD is unclear.
METHODS
We established streptozotocin plus high fat diet-induced DKD mice model with wild type or IL-37 transgenic mice. Masson and HE staining, immunostaining, and Western blot were used to observe renal fibrosis. In addition, RNA-sequencing was applied to explore the potential mechanisms of IL-37. In vitro, treatment of human proximal tubular (HK-2) cells with 30 mmol/L high glucose or 300 ng/mL recombinant IL-37 further elucidated the possible mechanism of IL-37 inhibition of DKD renal fibrosis.
RESULTS
In this work, we first verified the decreased expression of IL-37 in kidney of DKD patient and its correlation with clinical features of renal impairment. Moreover, IL-37 expression markedly attenuated proteinuria and renal fibrosis in DKD mice. Using RNA-sequencing, we found and confirmed a novel role of IL-37 in ameliorating fatty acid oxidation (FAO) reduction of renal tubular epithelial cells both in vivo and in intro. In addition, further mechanistic studies showed that IL-37 alleviated the FAO reduction in HK-2 cells and renal fibrosis in DKD mice through upregulating carnitine palmitoyl-transferase 1A (CPT1A), an important catalyzer for FAO pathway.
CONCLUSION
These data suggest that IL-37 attenuates renal fibrosis via regulating FAO in renal epithelial cells. Upregulation of IL-37 levels might be an effective therapeutic avenue for DKD.
PubMed: 37065609
DOI: 10.1159/000529460 -
Journal of Nephrology Nov 2022
Topics: Humans; Paraproteinemias; Kidney Diseases; Kidney
PubMed: 35687268
DOI: 10.1007/s40620-022-01362-5 -
Human Mutation Aug 2015Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal... (Review)
Review
Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.
Topics: Animals; Chloride Channels; Cohort Studies; Dent Disease; Genetic Association Studies; Humans; Male; Mice; Mice, Knockout; Mutation; Pedigree
PubMed: 25907713
DOI: 10.1002/humu.22804 -
Nephrologie & Therapeutique Jun 2015Cystinosis is a multisystemic autosomal recessive disorder characterized by an intra-lysosomal accumulation of cystine. It is due to a defect of cystine transport... (Review)
Review
Cystinosis is a multisystemic autosomal recessive disorder characterized by an intra-lysosomal accumulation of cystine. It is due to a defect of cystine transport through the membrane of the lysosome. The classical infantile form is characterized by a proximal tubulopathy, corneal cystine crystals and progressive renal failure, leading to end stage renal disease before 20 years of age in 90% of cases in historical cohorts. It is the most common cause of Fanconi syndrome in children. Due to recent progress in renal transplantation and to the specific treatment with cysteamine, patients survival improved significantly in the last years and adult nephrologists take care of such patients. However, disease evolution is characterized by other complications: endocrinological (hypothyroidism, diabetes, male hypogonadism), neuromuscular and of the central nervous system. Cysteamine delays the onset of these complications. A multidisciplinary team should take care of these patients, even if the nephrologist remains in first line. Apart from infantile form, there is a juvenile form, with a later onset, and an adult form, which may be only ocular, although renal involvement may be associated. The aim of this revue is to summarize actual knowledge of the disease to provide guidance to adult nephrologist to take care of his patients.
Topics: Adolescent; Adult; Cysteamine; Cystine Depleting Agents; Cystinosis; Fanconi Syndrome; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Insufficiency
PubMed: 25769364
DOI: 10.1016/j.nephro.2014.12.001 -
Critical Reviews in Oncology/hematology May 2020Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin (MIg) secreted by an otherwise asymptomatic or indolent... (Review)
Review
Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin (MIg) secreted by an otherwise asymptomatic or indolent B-cell or plasma cell clone, without hematologic criteria for treatment. The spectrum of MGRS-associated disorders is wide, including non-organized deposits or inclusions such as C3 glomerulopathy with monoclonal glomerulopathy (MIg-C3G), monoclonal immunoglobulin deposition disease, proliferative glomerulonephritis with monoclonal immunoglobulin deposits and organized deposits like immunoglobulin related amyloidosis, type I and type II cryoglobulinaemic glomerulonephritis, light chain proximal tubulopathy, and so on. Kidney biopsy should be conducted to identify the exact disease associated with MGRS. These MGRS-associated diseases can involve one or more renal compartments, including glomeruli, tubules and vessels. Hydrophobic residues replacement, N-glycosylated, increase in isoelectric point in MIg causes it to transform from soluble form to tissue deposition, causing glomerular damage. Complement deposition is found in MIg-C3G, which is caused by an abnormality of the alternative pathway and may involve multiple factors including complement component 3 nephritic factor, anti-complement factor auto-antibodies or MIg which directly cleaves C3. The effect of transforming growth factor beta and platelet-derived growth factor-β on mesangial extracellular matrix is associated with glomerular and tubular basement membrane thickening, nodular glomerulosclerosis, and interstitial fibrosis. Furthermore, inflammatory factors, growth factors and virus infection may play an important role in the development of the diseases. In this review, for the first time, we discussed current highlights in the mechanism of MGRS-related lesions.
Topics: Glomerulonephritis; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Paraproteinemias
PubMed: 32199132
DOI: 10.1016/j.critrevonc.2020.102926 -
Pathologica Aug 2021Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the...
Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the presence of a serum monoclonal spike (M-spike) of more than 3 g/dL or more than 10% clonal plasma cells in the bone marrow and at least one myeloma-defining event, such as hypercalcemia, anemia, bone lesions, or renal impairment. The kidney is a major target organ, and renal impairment is frequently the first manifestation of the disease. Renal damage occurs in up to 40% of patients and 10-20% will require dialysis. Monoclonal immunoglobulin light chains are the major causes of renal complications in multiple myeloma. Glomerular disease, with the deposition of monoclonal immunoglobulins or their components, includes monoclonal immunoglobulin deposition disease, AL or AH amyloidosis, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, immunotactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, tubulointerstitial diseases with the deposition of monoclonal immunoglobulins or their components, are constituted by light chain cast nephropathy, light chain proximal tubulopathy, and crystal-storing histiocytosis. We report the case of a 66-year-old woman who presented with albumin-predominant moderate proteinuria and renal failure. Serum and urine immunofixation electrophoresis showed monoclonal κ light chain in both. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving proximal tubular epithelial cells and crystal storing histiocytosis. Multiple myeloma with crystal storing histiocytosis was discovered in bone marrow biopsy. Thus, we present an unusual case of a myeloma patient presenting light chain proximal tubulopathy and crystal-storing histiocytosis both in the kidney and in the bone marrow.
Topics: Aged; Female; Histiocytosis; Humans; Kidney; Kidney Diseases; Multiple Myeloma; Paraproteinemias
PubMed: 34463673
DOI: 10.32074/1591-951X-154 -
Metabolites Mar 2020Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3.... (Review)
Review
Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.
PubMed: 32204545
DOI: 10.3390/metabo10030115 -
Expert Opinion on Pharmacotherapy 2016Tenofovir alafenamide (TAF) is is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations as compared to tenofovir disoproxil fumarate (TDF)... (Review)
Review
INTRODUCTION
Tenofovir alafenamide (TAF) is is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations as compared to tenofovir disoproxil fumarate (TDF) and such property suggests that TAF-containing regimens can improve renal and bone safety compared with TDF-containing regimens. Single tablet regimen elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) is the first coformulation that includes TAF in place of TDF. This review aims to provide an overview of its role in the treatment of HIV infection.
AREAS COVERED
This review covers pre-clinical and clinical data serached through Medline and Pubmed up to August 2015.
EXPERT OPINION
In terms of efficacy, E/C/F/TAF was found to be non inferior to E/C/F/TDF in naive patients, and more effective in patients switching from TDF-based regimens with efavirenz or boosted PI. In safety analyses, E/C/F/TAF was constantly found to be associated with significant improvement of renal function and urinary markers of proximal tubulopathy, and significant improvement of bone mineral density (BMD) as compared to TDF-containing regimens. E/C/F/TAF, as a new single tablet regimen, appeared to be promising for optimization of cART tolerability in HIV-infected patients.
Topics: Anti-HIV Agents; Bone Density; Clinical Trials as Topic; Cobicistat; Drug Combinations; Drug Resistance, Viral; Emtricitabine; HIV Infections; Humans; Quinolones; Tablets; Tenofovir
PubMed: 26642079
DOI: 10.1517/14656566.2016.1129401 -
Therapie 2021
Topics: Acyclovir; Humans; Kidney Diseases; Polyuria
PubMed: 32919761
DOI: 10.1016/j.therap.2020.08.001